Apparatus and methods for determining a property of a tissue

ABSTRACT

An apparatus for determining a thermal property of tissue includes a base unit with one or more energy source and at least two, preferably detachable, leads. The distal end of each lead, which is introduced into the tissue to be treated, has at least two longitudinally spaced temperature measuring elements to measure surrounding tissue temperature and at least two longitudinally spaced electrode surfaces for applying current to the tissue. Each distal end is also provided with an element which uses energy emitted by the sources of energy to heat up the surrounding tissue. The base unit has computing elements, current generating elements for generating an alternating current, and conductance determining elements for determining the tissue conductance between pairs of electrode surfaces based on the alternating current applied by the current generating elements to the tissue. Methods for using the device and leads for use in the device are also described.

FIELD OF THE INVENTION

The present invention relates to devices and methods for determining aproperty of a tissue.

BACKGROUND OF THE INVENTION

The liver is the most common site for tumours, which may be eitherprimary or secondary (metastases). In the Western world hepatic tumoursusually represent metastatic disease. The main cause of death forpatients with colorectal cancer (incidence: about new 6,000 cases inSweden in 2004) is the presence of liver metastases, which affect abouthalf of these patients. Breast cancer is the most common cancer in womenwith 6,900 new cases in Sweden in 2004. Prostate cancer is the mostcommon cancer in men with a current incidence of 9,900 patients/year inSweden. Lung cancer is the third most common cancer in Sweden, with3,200 new cases each year. Cancer of the pancreas accounts for about 2%of new cancer (900 new cases in Sweden in 2004) but has a poorprognosis. The relative 10-year survival rate is 1.3% for women and 1.5%for men. It is particularly important to find a better therapy for thisdisease. The above-mentioned cancers are examples of solid tumours thatare suitable for interstitial thermotherapy.

Therapy of Solid Tumours Standard Treatments.

Surgical resection is the mainstay of treatment with curative intent andis combined with adjuvant chemotherapy in diseases for which cytostaticdrugs have a demonstrable effect. Chemotherapy is the sole treatmentwhen the aim of treatment is palliative. Cytostatic drugs are usuallygiven systemically via the intravenous or oral routes but may also begiven regionally via intra-arterial infusion. Irradiation seems to beinferior to surgical resection with regard to local efficacy.

Minimally Invasive Therapies, Including Local Destruction Methods.

Some methods, like radiofrequency ablation (RFA), laser-inducedhyperthermia, cryotherapy and percutaneous ethanol injection (PEI) havebeen used rather extensively. Others like microwave coagulation orphotodynamic therapy, have been used less often in patients with solidtumours. Some, like electrochemotherapy or high intensity focusedultrasound, are being developed.

As compared to surgical resection, the advantages of local tumourdestruction include a) selective tissue damage which leads to a smallerimmunosuppression and a smaller release of growth factors, b) minimaltreatment morbidity and mortality, and c) the possibility to usechemotherapy in a more efficient way since chemotherapy can be startedbefore or at the time of local therapy.

Interstitial Laser Hyperthermia

Interstitial laser hyperthermia is a thermal technique, which destroystumours by absorption of light. Early experimental and clinical studiesused an Nd-YAG laser and bare fibres inserted into the centre of atumour, which created lesions that were 1.5 cm in diameter or less. Itwas soon apparent that clinical application would require larger lesionsand improved control of the tissue effect. Methods to improve lesionsize included multi-fibre systems, diffuser type fibres and vascularinflow occlusion. However the standard application of interstitial laserhyperthermia results in evaporisation and carbonisation of tissue andrelatively unpredictable tissue damage and lesion size. This has led tothe development of feedback control systems that monitor temperaturewithin tissue by means of temperature sensors placed at variousdistances from the point of treatment and which are interfaced with acomputer and a laser. The idea of these systems is that the laser outputis adjusted to return the monitored temperature to the desiredtemperature level when the monitored temperature rises above a settemperature or falls beyond a set temperature. It is thus possible tomaintain a substantially constant temperature over a desired period oftime at the measuring points which surround a known volume of tissue,which is intended to give a high degree of precision with respect toboth lesion size and type of cellular damage.

One of the advantages of feedback control of the treatment effect isthat it ensures reproducible and cytotoxic temperatures in the peripheryof tumour tissue. Another way to control lesion size is to use a doseplanning system, which enables lesion size to be calculated fordifferent tissues, output powers and treatment durations. Planning oflocal treatment can also be integrated with computer aided imageanalysis to give information about the size and location of tumours,vessels and bile ducts in 3-D views.

However such methods only determine the temperature in the vicinity ofthe temperature sensor(s) and give no information on whether therequired temperature has been achieved throughout the tissue that issupposed to be treated.

Interstitial Laser Thermotherapy (ILT)

Interstitial laser thermotherapy (ILT) is a variant of interstitiallaser hyperthermia where the focus is on killing tumour cells attemperatures of 46-48° C., i.e. at temperatures that do not cause tumourantigens to coagulate. Consequently ILT eventually produces cell deathwhile still allowing the presentation of intact tumour antigens. Thesecause an inflammatory local reaction and this can produce an efficientimmune response, both in rats and in human patients. This is in contrastto ablative techniques that use higher temperatures and thus causeinstantaneous necrotisation of the tissue. This is also in contrast totraditional hyperthermia that uses significantly lower temperatures,i.e.<42.5° C., and long exposure times.

For feedback control of the laser power one or more thermometers(thermistors or thermocouples) placed within the tumour and/or at thetumour boundary have commonly been used. One of the disadvantages withthis type of monitoring is that it requires interstitial positioning ofprobes and thus additional preparations. It is advantageous to encasethe monitoring device, e.g., a thermistor probe, with the laser fibreclose to the laser tip, avoiding separate punctures for temperaturemeasurement.

A problem that has occurred during feedback control using thermometersis that they only measure the local temperature and are unable to detectif overheating (or insufficient heating) occurs in tissue which is notclose to the thermometer. Overheating is undesirable as it may lead tocarbonisation and/or necrotic breakdown of the tissue. Carbonisation maybe present as a black layer surrounding the heat source which layerimpairs light penetration and reduces the distance that light canpropagate in the tissue. Rapid necrotic breakdown can cause poisoning.Insufficient heating is undesirable as it leads to ineffective treatmentof the tissue. Attempts to determine changes in the electricalproperties of tissue caused by heating have used implanted leadsprovided with electrodes to measure the impedance or transfer propertiesof the tissue and thermistors or thermocouples to measuretemperature—tissue impedance thermography. Using different frequenciesfor the current used in impedance measurements it is possible to measureimpedances in tissue local to the measuring electrodes as well as tissuefurther away. However the results have hitherto been consideredunreliable as the values of the impedance or transfer property obtainedwhen the temperature readings reach an elevated steady state (i.e. aconstant temperature, for example 46° C.) have changed continuously insuch a way that it appears that they are drifting—see FIG. 4 and FIG. 5.These figures show temperature and impedance against time at threedistances from the laser tip. Both graphs have a similar pattern showingthat changes in the measured tissue properties, in this case themeasured impedance, follow changes in the tissue temperature, and thatan irreversible change in the impedance occurs such that the impedanceat, for example, 40° C. at the beginning of the experiment is not thesame as the impedance at 40° C. at the end of the heating phase.Similarly FIG. 6, which shows conductance against temperature for atumour using information gathered from the experimental results shown inFIG. 2 “Conductance versus temperature at 44 kHz and 1 MHz for an EMT6tumour in vivo” in “The effect of hyperthermia-induced conductivitychanges on electrical impedance temperature mapping”, M A Esrick, D AMcRae, Phys. Med Biol. 39 (1994) 133-144, shows that the conductance ofEMT6 tumour tissue in vivo while being heated from 37° C. to 45/46° C.over a period of 19 minutes varies substantially linearly. From thisfigure it is possible to determine that the conductivity of this tissueat a current frequency of 44 kHz and 37° C. is around 3.5 mS, at 46° C.it is around 3.85 mS. Looking at this limited range the thermalcoefficient is 0.038 mS/° C. when measured at 44 kHz. When measured at 1MHz the conductivity at 37° C. is around 5.152 mS, at 45° C. it isaround 5.8 mS. Looking at this limited range the thermal coefficient is0.081 mS/° C. when measured at 1 MHz.

Cancer Therapy Using Laser Devices

Mueller et al (DE 3931854, 1991) presented an invention based on an MRItomograph for tumour location and monitoring during interstitial laserirradiation of tumours, e.g., in the liver, via quartz light conductingfibres. The invention was said to relieve the patient from surgery, longhospitalisation and to enable tumour removal with small side effects forthe patient. In this invention a multiplanar x-ray device is coupled tothe MRI tomograph to enable the fibres to be placed in the tumour usingpoint ion probes and the coordinates of the tumour to be determined byMRI tomography.

When performing an interstitial heat treatment of cancer tumours afeedback system that is able to present information to the userregarding the progress and outcome of the treatment is crucial. In priorart devices and methods, treatment is often performed based onexperience collected during previous treatments and the session time isset based on this knowledge. As a secondary means for treatment control,the tissue temperature may be monitored at a limited number ofmeasurement points. In many cases the treatment time is set to a periodlonger than that which is actually required as reliable means forfeedback regarding how the tissue is responding to the heating, the“tissue effects”, do not exist. For the same reason the desired resultcan not be obtained in many cases as the temperature distribution is notuniform in the target area and proper positioning of the temperaturesensors can not be ensured. As a temperature sensor can only sense thelocal temperature there is no way of checking if there are cold spotsoutside the local area, such cold spots being caused, for example, byblood vessels passing through the tissue and conducting away the heat.

SUMMARY OF THE INVENTION

Using the present invention it is possible to overcome at least some ofthe problems with prior art devices and methods for thermal treatment oftissue. In a first aspect of devices and methods in accordance with thepresent invention a tissue electrical property which varies withtemperature is monitored across a portion of the tissue being treatedwhile a feedback system controls the heating of the tissue to maintain adesired elevated tissue temperature, and the treatment is determined tobe complete when, at the maintained desired tissue temperature,substantially no further changes are detected in the monitoredelectrical property.

In a second aspect of devices and methods in accordance with the presentinvention, by initially establishing data regarding the tissueproperties and then combining this data with the temperaturemeasurements in known positions with regard to the heat source andfurther combining this information with two- and/or three-dimensionalelectrical property measuring (i.e. tissue transfer function and/orconductivity and/or impedance measurement) and correlating the actualchanges of these properties in the tissue to the expected change intissue properties based on the initial data, it is possible to extractinformation in a three-dimensional space regarding the non-reversibletissue effect that is a result of ongoing heat treatment. It issubsequently possible to determine the point in the treatment where thedesired tissue effect has been obtained and to inform the user that thetreatment is complete and successful. Furthermore it is also possible todetect when ongoing treatment is failing to achieve the expected changein tissue properties and to provide a signal to an operator that thetreatment is not proceeding as planned.

The present invention achieves this by providing implantable leads, eachprovided with impedance measuring electrode surfaces and temperaturemeasuring means, the leads being connectable to a base unit providedwith current generating means, measuring means for measuring theelectrical property of the electrical path between 2 electrode surfacesand control means, the control means being adapted to use electricalproperty and temperature readings from the leads to determine atemperature-dependent property of tissue in which the leads areimplanted.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows schematically a first embodiment of a thermal device inaccordance with the present invention;

FIG. 2 shows schematically a second embodiment of a thermal device inaccordance with the present invention;

FIG. 3 shows schematically a first embodiment of a digital system formeasuring the electrical properties of tissue;

FIGS. 4 and 5 show experimental results of impedance and temperatureagainst time during heating and cooling of tissue;

FIG. 6 shows experimental data which indicates that changes in tissueconductance are linear following slow heating to 46° C.;

FIGS. 7-11 show graphs showing the effect of temperature on conductivityfor different tissue models at two different current frequencies.

DETAILED DESCRIPTION OF THE INVENTION

In the following, directions are given in respect to the skin of apatient or the surface of an organ or tissue, thus the expression“above” means outside the skin or outside the surface of an organ orboundary of a tissue and is not dependent on the actual orientation ofthe patient, organ or tissue. Depths or levels or distances inside oroutside a patient or organ are, unless otherwise stated, measured in thedirection perpendicular to the skin of the patient or the surface of anorgan or tissue. Distances between components are measured fromedge-to-edge unless otherwise stated.

A first embodiment of a thermal device in accordance with the presentinvention is shown schematically in FIG. 1. Thermal device 1 comprises abase unit 3 and a plurality of insertable leads. In this example, inorder to avoid clutter in the illustration, the thermal device 1 hasbeen represented as having just two leads 5, 7 but in practice it ispossible that only one lead will be used for example for the treatmentof small tissue volumes and that more than 2 leads will be used forexample for the treatment of larger volumes of tissue. Larger number ofleads can be used if it is desired to reduce treatment time, or if theyare required for reasons of efficiency for example if the maximumextension of the tissue being treated is larger than can be reliablytreated with just two leads—typically when using lasers as the source ofenergy, leads are placed 2-3 cm apart. Preferably each lead 5, 7 iseasily detachable from base unit 3 so that leads can be easily replacedfor reasons of hygiene when a different patient is to be treated. Thedistal end of the each lead 5, 7 is intended to introduced though theskin 9 of a patient into, or into the vicinity of, the tissue to betreated e.g. tumour tissue 11. Preferably, to enable accuratepositioning, at least the portion of each lead intended to be insertedinto a patient is made sufficiently rigid so that it doesn't bend duringinsertion and use.

Base unit 3 may comprise one source of energy attached to a plurality ofleads, but preferably it comprises a plurality of sources of energy. Inthis embodiment one source of energy in the form of an infrared laser13, 15 is provided for each lead 5, 7, so in this example base unit 3comprises 2 lasers, the output of each laser 13, 15 being controllableindividually. Preferably each of said laser 13, 15 has a maximum opticaloutput power level in the region of 1-50 watts. The lasers preferablyprovide light energy of a wavelength that is efficiently absorbed byanimal tissue in order to heat said tissue. Preferably the lasersoperate in the wavelength range of 700 to 1300 nm, more preferably at805 or 1064 nm. Preferably each source is a solid-state semiconductorlaser as these have small dimensions and high efficacy. Alternativelyeach source of energy could be an Nd-YAG laser or similar, however thesedevices have the disadvantage of being less efficient and larger thansemiconductor lasers. Preferably the optical output power of each lasercan be independently controlled by a control system such as amicroprocessor or microcomputer 17, arranged in base unit 3, andprovided with appropriate operating software and hardware. Preferablybase unit 3 is provided with user input means such as at least onekeyboard 19, mouse, touch screen, tablet or the like, to enable a userto control the operation of the system and display means 21 such ascreen, monitor, light panel, or other display to provide measuredand/or calculated and/or processed information to the user. Suchinformation can include for example, one or more of the electricalproperties of the tissue between electrodes, the position of leads withrespect to each other and/or the target tissue to be treated, and tissuetemperatures.

The output laser light from laser 13 can be fed to an optical fibre 25which is inside lead 5 and extends to the distal end 27 of lead 5. Theoutput laser light from laser 15 can be fed to an optical fibre 29 whichis inside lead 7 and extends to the distal end 35 of lead 7. Each distalend 27, 35 is provided with a tissue heating element, in this example alaser light transparent energy emission window 32 resp 34 or bare fibretip at a short distance, e.g. between 0 and 40 mm, from the extremity ofthe distal end 27, 35. Preferably each window has a length L1 of between1 and 15 mm. In this embodiment an optical fibre tip 31, resp. 33through which laser light is transported to the distal end 27, 35 ispositioned in each window so that the laser light can leave the lead 5,7, be absorbed by, and heat the surrounding tissue. The optical fibretip can be in the form of a bare fibre, a diffuser or some other meansto guide the distribution of the laser light.

Each distal end 27, 35 is further provided with spaced apart distal andintermediate electrode surfaces, for example in the form of conductingelectrode plates, wires, projection, depressions or, as shown here,electrode rings 37, 39, resp. 41, 43. Electrode surfaces are made fromconductive media such as silver, platinum, gold or similar and during atreatment it is intended that said electrode rings are in electricalcontact with the tissue. Preferably the width of an electrode surface inthe longitudinal direction of a lead can be from 0.1 mm to 5 mm,preferably 0.5 to 2mm, although larger or smaller dimensions are alsoconceivable. Optionally a conductive paste, gel, liquid or similar maybe provided to the electrode surfaces during use to ensure reliableelectrical contact. Distal electrode rings 37, 41 may be placed closerto the extremity of each lead 5, 7 than said windows 32, 34 and arepreferably within a distance L2 of 0-10 mm from the distal end ofwindows 32, resp 34. Intermediate electrode rings 39, 43 are positionedfurther away from the extremity of their respective leads preferably ata distance of L3 of 0-40 mm from the proximal end of window 32, 34. Thusin this embodiment of the present invention each window 32 resp. 34 maybe positioned between a pair of electrode rings 37, 39 resp. 41, 43.

Note that if, as disclosed above, window 32, 34 is placed at theextremity of the lead, (i.e. 0 mm from the extremity) then the pair ofelectrode surfaces (and any further electrode surfaces) are positionedfurther away from the extremity than the window and are longitudinallyspaced apart. Preferably the longitudinal distance between a pair ofneighbouring electrode rings on a lead is less than 55 mm, morepreferably less than 40 mm, e.g. 6 mm or 10 mm, and preferably isgreater than 3 mm.

Electrode rings 37, 41 are longitudinally separated from electrode rings39, 43 by a distance L1+L2+L3. While L1, L2 and L3 for lead 5 may besame as L1, L2 and L3 for lead 7 and, in the event additional leads areused, all additional leads it is not a necessity but to permit accuratepositioning it is necessary that the distance between electrode surfaceson each lead is known.

Each electrode ring 37-43 is connected by its respective electricalconductor 45, 47, 49, 51 to the switchable output of a current generator50 and the switchable inputs of a measuring circuit 52 preferably ableto measure an electrical property of the electrical path between anypair of electrode rings. In order to illustrate the present invention anembodiment is now described in which circuit 52 is a conductancemeasuring circuit of the type well-known in the prior art whichcomprises an amplifier and analogue-to-digital converter. The use ofother measuring circuits which measure one or more of the propertiesconductance, resistance, impedance and capacitance is also conceivable.Current generator 50 is controllable to produce alternating current ofknown amplitude and, preferably, known phase and, preferably, isswitchable between at least two frequencies, one low frequency, forexample less than 500 Hz or 1 kHz or 5 kHz or 10 kHz or 50 kHz or 100KHz and one high frequency e.g. greater than 200 kHz or 500 kHz or 1 MHzor 2 MHz. The possibility of using different frequencies duringconductance measuring allows the conductance of different volumes oftissue to be measured (and the conductivity to be calculated if theconduction path length is known)—a form of tomography. This is becausethe current path between electrodes depends partly on the frequencyused—lower frequency currents, e.g. 1 kHz, follow curved paths betweenelectrodes while higher frequencies, e.g. 100 kHz, follow more directpaths. Current generator 50 and conductance measuring circuit 52 arecontrollable by control system 17 so that, preferably, it is possible tomeasure the conductance between any pair of electrode rings 37-43, 71-81and at any desired frequency. This can be achieved, for example by usingdigital storage means and a digital to analogue converter 56. An exampleof such a digital system for measuring the electrical properties oftissue, shown schematically in FIG. 3, could comprise digital storagemeans in the form of digital memory 54 containing a signal loop whichproduces a cyclical signal which sweeps from a low frequency (e.g. 500Hz) to a high frequency (e.g. 200 kHz) over a period of a few seconds,e.g. 5 seconds or 10 seconds and then repeats. This signal istransmitted to a digital to analogue converter 56 connectable by amultiplexer 58 to any pair of electrode rings—which electrode ringscould be on the same lead or on different leads. The resultingelectrical properties of the tissue between this pair of electrode ringsare then sampled and converted to a digital signal by signal conditioner60 and the values of the properties recorded in the memory 54 againstthe signal which caused them. As shown in FIG. 3, these recorded signalscan be used to produce a representation 62, 64, 66 of the transferfunction in the frequency domain of the tissue that the electrodes arein. Each type of tissue has a certain transfer function depending ondensity, cell size, vascularity, etc. The electrical properties e.g. theconductance or impedance or transfer function of the tissue will changeduring thermal treatment as the physical properties of the tissue changeand thus the transfer function in the frequency domain of the tissuewill change as the tissue changes. Reference 62 shows a hypotheticalrepresentation in the frequency domain of tissue in a first state, e.g.before thermal treatment and reference 64 shows a hypotheticalrepresentation of the same tissue during a step in thermal treatment ofthe tissue where the temperature of the tissue is higher than that ofthe tissue in the first state. Reference 66 shows a hypotheticalrepresentation in the frequency domain of the same tissue after it hasbeen killed by thermal treatment.

An improved digital system for measuring the electrical properties oftissue could have two signal channels. The first channel having a signalloop of the type mentioned above and the second channel containing asynchronisation signal which is used to synchronise the measurement andto improve the resolution in time. The synchronisation signal can beorganised as one synchronisation pulse per sweep (in combination with acontroller system that ensures that the following samples are timedcorrectly) or one pulse for each sampling point. The solution is verysimple and in spite of this it will enable very complex measurements. Adigitalised sweep signal, for instance from 500 Hz or 1 kHz to 100 kHzor 2 MHz or white noise or pink noise or the like having a certainpattern is stored in the digital memory device. The digital data is fedto a two channel digital to analogue converter in which channel 1 holdsthe sweep signal and channel 2 contains a synchronisation signal. Thesweep signal is feed to an amplifier, for instance a variable gainamplifier which may be controlled from the control system in order toadjust the amplitude to the desired level. The amplifier signal is fedto a multiplexing device that allows the signal to be feed to any of theselected electrode pairs. An amplifier circuit measures the appliedvoltage and resulting current and phase. A resistor is connected inseries with the signal path to allow current measurement. Ananalogue-to-digital converter and timing circuit samples the signal attimes synchronised by means of the synchronisation signal with the sweeppattern fed to the electrodes. Digitised signals are stored in memoryalong with synchronisation information. The stored information can befed to the control system which preferably is adapted to performingsignal processing, for example an averaging of the repeated signals,that will improve the signal quality.

In the following the symbol ‘Z’ is used to refer to the measuredelectrical properties of tissue through which electricity is conductedbetween two sensing electrode. If measurements are taken at just onefrequency then Z could be the conductance or impedance of the tissue. Ifmeasurements are taken at more than one frequency then Z would be atransfer function of the tissue It is possible to determine a transferfunction in a number of ways, for example by using a number forfrequencies (as described above), scanning, white or pink noise or thelike in combination with FFT or FT ((Fast) Fourier Transformation)). Inthe following description, the device and methods of using it will beillustrated by examples where the conductance of tissue is measured butit is understood that the invention is also applicable to devices andmethods where impedance and/or a transfer function of tissue ismeasured.

Normally the conductance of tissue increases with heating and thisincrease is substantially fully reversible upon cooling back to 37° C.if the tissue is only heated to approximately 5-6° C. above its normaltemperature (where 37° C. is the normal temperature for human tissue).Further heating, for example to 9° C. above the normal temperature, willcause cell death (without causing cells to burst) which causes someirreversible changes in conductance along with some reversible changesin conductance—i.e. the conductance of the dead tissue when cooled backto 37° C. is not the same as its conductance at 37° C. before it washeated.

At least each distal and intermediate electrode ring 37-43 is preferablyprovided with its own thermal sensor such as a thermistor 55, 57, 59,61, so that the temperature in the vicinity of the electrode ring can bemeasured. It is also conceivable to provide other electrode rings withtheir own thermal sensors. By attaching the thermal sensor to anelectrode surface or building it into the electrode surface the localtemperature at which conductance measurements are being made can bereliably determined. As an alternative a thermal sensor can be providedadjacent to an electrode surface.

Each thermistor 55-61 is connected by its respective pair of electricalconductors 63, 65, 67, 69 to a control circuit 71 of control system 17which permits control system 17 to determine the temperature of eachthermistor 55-61. Control circuit 71 can, for example, comprise aconventional Wheatstone bridge circuit of the type well-known to beuseful for measuring temperature when used in connection withthermistors.

A plurality of depth sensing electrode surfaces for example in the formof conducting electrode plates, wires, projections, depressions or, asshown here, such as electrode rings 71, 73, 75 resp. 77, 79, 81 areplaced on each lead 5, 7. Electrode rings are made from conductive mediasuch as silver, platinum, gold or similar. Preferably the width of anelectrode ring in the longitudinal direction of a lead can be from 0.1mm to 5 mm, preferably 0.5 to 2mm, although larger or smaller dimensionsare also conceivable. Optionally a conductive paste, gel, liquid orsimilar may be provided to the electrode surfaces during use to ensurereliable electrical contact. First depth sensing rings 71, 77 arepositioned at a predetermined distance from the respective intermediateelectrode rings 39, 43, e.g. at a distance of between 5-15 mm, e.g. 5 mmor 10 mm or 15 mm, from intermediate electrode rings 39, 43 in thedirection towards the proximal end of the lead. Second depth sensingrings 73, 79 are positioned a further distance away from the distal end,e.g. at a distance of between 5-15 mm e.g. 5 mm or 10 mm or 15 mm, fromfirst depth sensing electrode rings 71, 77. Similarly third depthsensing electrode rings 75, 81 and any further depth sensing electroderings (not shown) are positioned further away from the distal ends andpreferably with the same separation of between 5-15 mm e.g. 5 mm or 10mm or 15 mm, from the adjacent depth sensing electrode ring. It is notrequired that the distance between rings is the same but the distancebetween the rings on each lead has to be known or standardised in orderto allow accurate positioning by triangulation. The actual distancebetween depth sensing electrode surfaces can be selected depending onthe accuracy of depth measurement required. The closer together that thesurfaces are, then the more accurate the depth measurements will be.

One or more leads may optionally be provided with readable memory 78 andthe information regarding electrode surface positions on the lead can bestored in the memory of the lead. Preferably this information isinputted into the memory by the manufacturer of the lead. During use ofsuch a lead the control unit can extract the information regardingelectrode positions from the lead and use it in triangulationcalculations. Preferably the memory is resistant to X-ray and gammaradiation in order to permit sterilisation of the leads. Preferably thememory is ferro-magnetic random access memory (FRAM). In the event thatleads without memory containing information on electrode positions areused or the memory is not accessable by the control unit, preferablymeans are provided for user input of such information to the controlunit.

Each depth sensing electrode ring 75, 81 is connected by a conductor(not shown for clarity of illustration) to the switchable output ofcurrent generator 50 and the switchable inputs of conductance measuringcircuit 52. Preferably conductance measuring circuit 52 is arranged tobe able to measure the conductance between any pair of distal,intermediate or depth sensing electrode rings at any desired frequency,e.g. frequencies between 500 Hz and 2 MHz.

Thermal device 1 is intended to thermally treat tissue, especiallydiseased tissues, for example a tumour. In order to do this, the lead orleads which will be used to heat tissue have to be accurately placedboth with respect to the unhealthy tissue e.g. the cells of a tumourwhich has to be killed and, in the case two or more leads are used, alsowith respect to each other. In a first illustration of a method forpositioning leads, it is intended that at least the window 32, 34, anddistal electrode ring and intermediate electrode ring 37, 39, 41, 43(and their respective thermal sensors 55, 57, 59, 61) of each of twoleads is to be placed inside a tumour 11. In some cases the leads areintended to be positioned such that the window 32, 34, and distalelectrode ring and intermediate electrode ring of each lead are outsidethe tumour—this is illustrated in FIG. 1 by a tumour 11′ shown in dashedlines. The position of the tumour in relation to other features of thepatients body is assumed to be known, e.g. from previously orsimultaneously performed imaging. One or more leads 5, 7 are positionedon the skin of the patient immediately above the tumour and pushedthorough the skin 9 and healthy 10 tissue of the patient towards thetumour. As the exact position and/or size of the tumour may have changedsince the imaging was performed and it may be difficult or impossible todetermine the boundaries of the tumour with imaging methods, it isuseful to determine when the windows 32, 34, and if the extent of thetumour allows, the distal ends 27, 35 and distal and intermediateelectrode rings 37, 39, 41, 43 are inside the tumour 11. The relativepositioning of the electrodes rings (and hence the leads they areattached to) can be determined by measuring the conductance betweenpairs of electrode rings. Normally the conductivity and transferfunction of tumour tissue is different from healthy tissue. Duringinsertion of a lead e.g. lead 5, the conductance between distal andintermediate electrode rings 35 and 37 is monitored. Lead 5 ispositioned above the tumour 11 and is inserted through the skin towardsthe tumour 11. Distal electrode ring 37 enters the body of the patientfirst and it is then followed by intermediate electrode ring 39. Nocurrent will flow between distal electrode ring 37 and intermediateelectrode ring 39 until intermediate electrode ring 39 comes intocontact with tissue, at which point a certain conductance value will bemeasured between electrode rings 37 and 39. Next the conductance betweenintermediate electrode ring and first depth sensing electrode ring 71can be monitored. No current will flow between them until first depthsensing electrode ring 71 comes into contact with the skin of thepatient. As the lead is introduced further into the patient, second,third and any further depth sensing electrode rings will come intocontact with the patient's tissue and the depth of the lead in thepatient can be determined from knowledge of which electrode ring pairshave a conductance which indicates that they have entered the patient.Thus if the lead is intended to be inserted so that the distal end isintended to be 40 mm below the skin of the patient, and there is a depthsensing electrode ring positioned 30 mm from the distal end and afurther depth measuring electrode positioned 40 mm from the distal end,then, assuming that the lead has been inserted perpendicularly to theskin of the patent, the depth of the distal end will be 40 mm below theskin of the patient when the further depth measuring electrodepositioned 40 mm from the distal end comes into contact with the skinand current, preferably alternating current, starts to flow between thedepth sensing electrode ring positioned 30 mm from the distal end andthe further depth measuring electrode positioned 40 mm from the distalend.

During insertion of the lead, the conductance between some or all of thepermutations of combinations of pairs of electrode rings can bemonitored. This can be used to see if the electrical properties of thetissues through which the lead is passing are the same. Normally healthytissue has a different conductivity to that of tumour tissue. In thosecases, by monitoring changes in the conductance as a lead is beinginserted into tissue, it is possible to determine changes inconductivity and hence detect when the lead has entered, or is close to,tumour tissue. For example, during insertion of the lead the conductancemeasured between the distal electrode ring and intermediate electrodering is monitored or sampled after both electrode rings have enteredhealthy tissue. The conductance remains substantially the same untildistal electrode 37 enters the tumour, or is in the immediate vicinityof the tumour, at which point the conductivity may change. If it doeschange, then it will continue to change until the intermediate electrodering 39 closely approaches or enters the tumour (assuming that thetumour is deep enough to contain both distal and intermediate electroderings). As long as both distal and intermediate electrode rings 37, 39remain in the area of the tumour further movement of the lead should notresult in any significant change in conductance between electrode rings37 and 39. If the conductance does change unexpectedly then this couldbe a sign that there is a problem, for example that the distal electrodering has exited the tumour field, or entered a blood vessel inside thetumour or there is a malfunction, and appropriate action, such asrepositioning a lead or replacing a lead, would need to be taken.

Once lead 5 is at the required depth inside the tumour and if more than1 lead is to be used in the treatment then the same procedure can befollowed with lead 7 and any other leads. Preferably during insertion oflead 7 (top aid in positioning the lead) and/or once lead 7 has enteredthe tumour (to determine its position with respect to other leads) thedistance between electrode rings on the implanted leads can be measuredby triangulation - that is by measuring the conductance or transferfunction between pairs of electrode rings on different leads and usingthis to calculate the distance between each such electrode pair. Thereadings between pairs of electrode surfaces can be processed in orderto determine the position of the leads both with respect to the tumour(assuming its position is known) and with respect to any other leads. Asthe distance L2 between the electrode rings 37, 39 and 41, 43 is known,it is possible to determine the electrical properties of the tumourtissue, preferably by measuring its conductance at least two frequenciesto determine its transfer function. The distance between electrode ring37 on lead 5 and electrode ring 41 on lead 7 can be determined bymeasuring the conductance and/or transfer function Z (37-41) betweenthis pair of rings. The distance between electrode ring 39 on lead 5 andelectrode ring 43 on lead 7 can be determined by measuring theconductance and/or transfer function Z (39-43) between this pair ofrings. If Z (37-41) and Z (39-43) are the same then electrode ring 37and electrode ring 41 are the same distance apart from each other aselectrode ring 39 is from electrode ring 43. This distance can becalculated by dividing the values of these electrical properties(conductance and/or transfer function) by the electrical propertiesdetermined previously for the known distance between the distal andintermediate electrodes on the same lead. In order to determine if thedistal ends 27, 335 of leads 5 and 7 are at the same depth in thepatient the conductivities and/or transfer functions between diagonallyopposed pairs of electrode rings can be measured, i.e. theconductivities and/or transfer functions Z (37-43) and Z (39-41). Ifthese are the same then the diagonal distance between electrode rings 37and 43 is the same as the diagonal distance between electrode rings 39and 41. If the measurements show that Z (37-41) and Z (39-43) are thesame and also that Z (37-43) and Z (39-41) are the same then it can beassumed that leads 5 and 7 are parallel and have their distal ends atthe same depth. If (37-41) and Z (39-43) are not the same and/or Z(37-43) and Z (39-41) are not the same then it is possible to calculatethe relative position of the leads with respective to each other, i.e.how far apart they are, whether they are inclined with respect to eachother and if so, at which angle(s). Preferably such calculations aremade at regular intervals during insertion of the leads. Said intervalsare preferably less than 10 seconds, more preferably less than 2 secondsand most preferably are less than 1 second, thereby allowing real timemonitoring of the position of electrodes so that the operator implantingthe leads can be given accurate and timely information regarding theposition of the leads as they are being implanted. Of course it is notalways intended that leads should be parallel or at the same depth, astheir intended positions are dictated by the, probably irregular, shapeof the tumour being treated. Using the principal of triangulation asdescribed above it is possible to verify if leads have the intendedpositioning with respect to each other and, preferably, the tumour.

It is conceivable that the collected signals and the resulting dataincluding, but not limited to, calculated distances and angles betweenleads, signal phase, voltage and/or current amplitudes, tissueproperties such as impedance, conductance and tissue effect temperaturecould be presented to an operator through an operator interface. If anumber of leads are used and any pair of electrodes can be selected alarge number of different current paths can be selected. Using theresult obtained for the different paths a two-or three-dimensionaltomographic image can be calculated based on the results. Furthermoretwo electrodes can be used to feed current though the tissue and theremaining electrodes can be used to monitor the resulting voltages. Thiscan be used to further enhance the image resolution both in spatialresolution quality and in precision. The information could be presentedin numerical form, in graphical form and/or as a calculated tomographicmap in two- or three-dimensions. The choice of presentation may dependon the number of current paths used to inform the user about the currentstate of the tissue and the progress of the ongoing procedure. By usinga sufficiently fast computer and appropriate software the informationcould be presented in real-time, i.e. the collected signals areprocessed and updated information presented to the operator in a shortperiod of time ranging from less than a second to 20 seconds.

A second embodiment of a thermal device in accordance with the presentinvention is shown schematically in FIG. 2. In this embodiment of adevice in accordance with the present invention the depth of each leadinside a patient is determined with the help of movable electrodes. Eachlead 205, 207 is provided with a movable sleeve 281, 283 through whichthe distal end of the respective lead passes. Sleeves 281, 283 arelockable in place on their respective sleeves by a locking means such asa locking screw 285, 287. The distal end of each sleeve 281, 283 isprovided with a sleeve-mounted electrode 289, 291 which is intended tobe in contact with the patient's skin or the tissue being treated duringtreatment. Each lead 205, 207 is provided with a graduated scale 293,295 which can be used to read off the distance that the sleeve-mountedelectrode 289, 291 is from the centre of the window of the lead. Beforeinsertion of each lead 205, 207 into the patient, the working depths forthe lead is determined, e.g. by scanning to determine the position ofthe tissue being treated and the appropriate depth for each lead to bepositioned at. The appropriate depth can be determined, for example, asthe depth that the centre of the window should be from the skin of thepatient or, as a second example, as the depth that the centre of thewindow should be inside an organ, the depth being measured from thesurface of the organ.

In a method for using the device in accordance with the secondembodiment of the present invention when the depth that the windowshould be from the skin is known, each lead 205, 207 is passed through arespective sleeve 281, 283 until a reference point of the sleeve, e.g.its upper rim, 297, 299 is adjacent the mark on the scale whichcorresponds to the desired working depth. The sleeve is then locked atthis position. For example if the centre of the window is supposed to be15 mm below the skin of the patient then the sleeve is locked with itsreference point adjacent the 15 mm mark of the scale so that thesleeve-mounted electrode is positioned 15 mm away from the centre of thewindow. The value of the transfer function of the tissue measuredbetween the sleeve-mounted electrode and a ring electrode e.g. ringelectrode 37 on the same lead will be infinity when there is noelectrical contact between them. The lead can be inserted into thepatient until the sleeve-mounted electrode 289 comes in contact with theskin of the patient at which point the lead 205 is at the desiredworking depth. This point can be determined from the step change in thetransfer function signal which occurs when electrical contact becomesestablished between the e.g. ring electrode 37 and the sleeve-mountedelectrode. Second and subsequent leads can be positioned in the sameway. The correct positioning of leads 205, 207 with respect to eachother and/or the determination of their actual positions can be achievedby triangulation as described above with reference to the firstembodiment of the invention.

In a method for using the device in accordance with the secondembodiment of the present invention when the depth that the windowshould be from the surface of an organ, e.g. the surface of the liver,is known, each lead 205, 207 is passed through a respective sleeve 281,283 until a reference point of the sleeve, e.g. its upper rim, 297, 299is adjacent the mark on the scale which corresponds to the desiredworking depth, i.e. the distance between the surface of the organ andthe window. The sleeve is then locked at this position. For example ifthe centre of the window is supposed to be 20 mm below the surface ofthe organ of the patient then the sleeve is locked with its referencepoint adjacent the 20 mm mark of the scale so that the sleeve-mountedelectrode is positioned 20 mm away from the centre of the window. Thevalue of the transfer function of the tissue measured between thesleeve-mounted electrode and a ring electrode e.g. ring electrode 37 onthe same lead will be infinity when there is no electrical contactbetween them. The lead can be positioned above the organ and be insertedinto the patient. During insertion into the patient the transferfunction and/or conductance between distal and intermediate electrodescan be measured in order to determine the conductance and/or transferfunction for the tissues and organs that the lead passes through. Thevalues for these tissues and organs can then be compared to the valuesobtained between the intermediate electrode and the sleeve-mountedelectrode to identify the point at which the sleeve-mounted electrode289 comes in contact with the surface of the organ to be treated—atwhich point the lead 205 is at the desired working depth. In otherwords, this point can be determined from the step change in theconductance and/or transfer function signal which occurs when electricalcontact becomes established between the intermediate electrode and thesleeve-mounted electrode. Second and subsequent leads can be positionedin the same way. The correct positioning of leads 205, 207 with respectto each other and/or the determination of their actual positions can beachieved by triangulation as described above with reference to the firstembodiment of the invention.

In a method for using the device in accordance with the secondembodiment of the present invention when the depth that the windowshould be from the surface of an organ is known, each lead 205, 207 ispassed through a respective sleeve 281, 283 until a reference point ofthe sleeve, e.g. its upper rim, 297, 299 is adjacent the mark on thescale which corresponds to the desired working depth. The sleeve is thenlocked at this position. For example if the centre of the window issupposed to be 10 mm below the surface of the organ, e.g. the liver,then the sleeve is locked with its reference point adjacent the 10 mmmark of the scale so that the sleeve-mounted electrode is positioned 10mm away from the centre of the window. The lead can be inserted into thepatient and the transfer function between the ring electrodes monitored.When the two ring electrodes enter the healthy tissue of the organ beingtreated then a steady transfer function value for healthy tissue shouldbe recorded between them until the distal ring electrode enters diseasedtissue, e.g. tumour tissue, having a different transfer function, atwhich point the value of the measured transfer function will changeconstantly until the intermediate electrode and the distal electrodeboth are in the same type of diseased tissue. The transfer function ofthis tissue can be recorded and the value of the transfer functionbetween the sleeve electrode and the intermediate electrode can now bemonitored. When the sleeve-mounted electrode 289 comes in contact withthe diseased tissue the transfer function value that is being measuredbetween the sleeve-mounted electrode and the intermediate electrode willcorrespond to that of the diseased tissue and it can be inferred thatthe sleeve-mounted electrode has just entered the diseased tissue andthe window is at the correct working depth. Second and subsequent leadscan be positioned in the same way. The correct positioning of leads 205,207 with respect to each other and/or the determination of their actualpositions can be achieved by triangulation as described above withreference to the first embodiment of the invention.

Once leads have been correctly positioned in the diseased tissue,treatment of the tissue can be performed.

Theoretically, if tissue was only reversibly affected by temperatureeven when heated to 46° C. the tissue could be heated to 46° C. andtemperature responses similar to those shown in FIG. 7 (temperature andconductance versus time when conductance is measured at 44 kHz) and FIG.8 (temperature and conductance versus time when conductance is measuredat 1 MHz) would be obtained. These models show such a theoretical tissuebeing heated from about 2 minutes to about 32 minutes to a desiredtemperature of 46° C. with slightly imperfect feedback control so thatthe actual temperature oscillates above and below the desiredtemperature. The heating is terminated after 32 minutes, The tissue isallowed to cool and the model shows that the conductance at 37° C. afterthis prolonged heating is the same as the conductance at 37° C. beforeheating. An equivalent electrical schematic behaving like tissueaccording to this theoretical model is very complex as it has afrequency dependency and a thermal coefficient. It thus consists ofcapacitors, inductors, resistors and thermistors connected in series andin parallel. However when looking at one specific frequency, thefrequency dependent components can be removed and a very simplifiedequivalent circuit can be used.

Thus tissue which is unaffected by heat can be modeled as:

The figure above describes the resistance of a piece of tissue at acertain frequency and in a limited temperature window. It has a startingresistance (mainly R2) and a temperature dependency (variable resistanceR1) with a negative temperature coefficient (i.e. comparable to that ofa negative temperature coefficient (NTC) thermistor). Thus when thetemperature increases the conductivity will go up (i.e. the resultingresistance/impedance goes down).

However in real life tissue, when exposed to heat, above a certaintemperature irreversible changes in the properties of the tissue occur.The conductivity will shift in a way that can not be explained in thesimplified schematic above. A model for this real-life tissue is asfollows:

-   -   Simplified equivalent schematic after heat treatment for real        life tissue

In this figure RX has been added. RX is the irreversible influence (the“tissue effect”) of a heat treatment at a certain temperature for acertain time.

Normal  Conductivity = Starting  conductivity + (Tcoef ⋆ temp  rise) + integrated  (Tissue  Effect  Constant * (Temp  rise * time))Or  (@44  kHz  for  tumour  EMT6  tissue)3.5 + (0.038 * (T_(act) − 37)) + ∫_(t₀)^(t_(n))T_(eff) * (T_(act) − 37) * T_(slot)

When T_(slot) is a time slot in which a measurement is taken.

Adapting this model to have the characteristics of EMT6 tumour tissueand plotting temperature and conductance against time, assuming that ittakes 30 minutes for all the tissue in the conductance path beingmeasured to be heated at 46° C. and thereby fully irreversibly affectedby the elevated temperature, would give curves similar to those shown inFIG. 9 (temperature and conductance versus time when conductance ismeasured at 44 kHz) and FIG. 10 and FIG. 11 (temperature and conductanceversus time when conductance is measured at 1 MHz), where the line“normal behaviour” relates to the real life tissue and “expectedbehaviour” relates to theoretical tissue of the type shown in FIGS. 7and 8 which does not suffer irreversible thermal changes. These reallife tissue curves show that in real life tissue the conductance risescontinuously but at decreasing rates before leveling off. The steepest,first part of the curve up to about 6.5 minutes shows the reversiblechange in conductance caused by heating. There then follows a lesssteep, second part of the curve up to 30 minutes which representsincreasing numbers of cells in the tissue in the conductance path beingmeasured undergoing irreversible changes i.e. are being killed. Thethird part of the curve, from 30 minutes until heating is terminated ataround 33 minutes, has an average slope which is horizontal, and thisindicates that all the cells in the tissue in the conductance path beingmeasured have undergone irreversible changes i.e. are dead. In this partof the curve, continued heating with feedback control will not cause anyfurther changes in the tissue in the conductance path being measured,and the difference in relative conductance between the measuredconductance and the expected conductance (that is, the conductance thatwould be expected if the tissue did not undergo irreversible thermaleffects) is at a maximum. At this point further treatment will not haveany beneficial effect in the local area as the tissue in that region hasalready been killed.

A first embodiment of a device in accordance with the present inventionfor the thermal treatment of tissue comprises software and hardwaremeans e.g. a computer, for running the software for automaticallymeasuring the electrical property of tissue into which leads connectedto the device have been positioned.

The software performs the following steps:

activating sources of energy 13, 15 to provide energy to tissue heatingelements 32, 34. This causes the tissue in the region near the heatingelements to be warmed;monitoring the temperature sensed by thermal sensors 55, 57, 59, 61 andcontrolling the heat provided to tissue heating elements 32, 34 so thata predetermined desired temperature is detected and maintained at saidthermal sensors 55, 57, 59, 61. Preferably there is a feedback systemwhich prevents large swings in the temperature measured by the thermalsensors;measuring, storing and processing the value of an electrical propertybetween electrode pairs to determine changes in the measured electricalproperty, wherein said electrodes are positioned on different leads.This permits the change in the electrical property in the electricalpath between the leads to be measured;deactivating said sources of energy when, after having started changing,said value of an electrical property ceases to change for apredetermined period of time, for example once the property has remainedsubstantially the same for 1 minute or 2 minutes. The electricalproperty should change continuously as the heat spreads and the regionof heated tissue increases and more and more of the tissue in theelectrical path in region is killed. Once no further changes in theelectrical property can be detected there is no need to prolong theheating as the absence of change indicates that the maximum effectpossible by heating in the region between the leads has been achieved,the heating can be terminated and, optionally, a signal made to signifythat treatment has been terminated. This signal can alert an operatorthat the treatment is finished and the leads may be removed from thepatient.

In a second embodiment of a method to determine the thermal propertiesof a tissue in accordance with the present invention, once leads havebeen correctly positioned in the diseased tissue, the conductancethermal coefficients (T_(coef)) of the tissue can be measured.Conductance thermal coefficients are defined by the formulaT_(coef)=ΔZ_(f)/Δt, where t is the tissue temperature in degrees C., andZ_(f) is the conductance measured at frequency f .

Firstly, the reversible conductance thermal coefficient (rT_(coef)) ofthe tissue is determined by applying heat for a short period of time,which is sufficiently short such that the tissue is not heated totemperature where irreversible effects take place in the tissue.Naturally the length of the period of time that the heat can be appliedfor depends amongst others, on the energy delivered by the heatingmeans, the distance between leads and the thermal properties of thetissue being heated. Preferably this heating phase is controlled andmonitored by suitable control, recording and processing software in thecontrol means, arranged so that heating is terminated if the thermalsensors adjacent to the heating means in the tissue register atemperature above a predetermined maximum value, for example 4° C. or 5°C. above the normal tissue temperature This predetermined maximum valueis chosen to be sufficiently low that there is no risk of irreversibleeffects occurring in the tissue. In the following it is assumed thatirreversible effects take place above 43° C. and that tissue cells willbegin to undergo cell death when exposed to a deadly thermal dose whichis greater than a certain value. For example for tumour cells thisdeadly thermal dose is assumed to correspond to being exposed to atemperature of 46° C. for 30 minutes. Temperatures between 43° C. and46° C. would therefore require exposure times which are longer than 30minutes and temperatures above 46° C. would require exposure times ofless than 30 minutes to initiate cell death. By using thermal sensorswhich are positioned adjacent to the heating element, and hence shouldundergo the highest temperature rise it is possible to ensure that notissue is heated above the predetermined maximum value. Having thethermal sensors attached to the electrode surfaces used for measuringthe electrical property of the tissue ensures that the exact temperatureof the electrode surface is known. During this heating phase thetemperature and conductance in the near field (i.e. between electrodesurfaces and their associated thermistors which are situated on the samelead) are monitored. The heating is switched off and the temperature andconductance allowed to return to the initial value while beingmonitored. Preferably this is repeated in order to ensure that noirreversible changes take place in the tissue. As the heating isrelatively short no permanent tissue effect should be produced. Theundamaged (or reversible) conductance thermal coefficient of the tissuecan be calculated by software in said control unit based on the changesin conductance and temperature. For example, using the experimental datamentioned above for EMT6 tumour in vivo, the software could determinethat the conductivity at 44 kHz and 37° C. is 3.5 mS, with a thermalcoefficient of 0.038 mS/° C., and the conductivity at 1 MHz at 37° C. is5.152 mS with a thermal coefficient of 0.081 mS/° C.

A second step is performed in which heating is intended to produce nearfield irreversible effects, namely death of the diseased tissue, bycontrolled heating. The control, recording and processing softwarecauses heat to be applied to the tissue at a preset temperature above42.5 ° C. which is preferably below 48° C., further preferably below 47°C. and most preferred at 46° C. The preset temperature is chosen so thatit will result in cell death after a period of time but does not causetumour antigens to coagulate. This preset temperature is selected toavoid instant necrotisation, carbonization, coagulation or ablation ofthe tissue and thus destruction of the tumour antigens.

During this heating the near field tissue conductance and thetemperature are monitored, for example at 10 second intervals. Heatingis continued until no further changes in conductivity occur in the nearfield paths being monitored, i.e. the average gradient of conductanceagainst time is zero. When the conductance gradient is substantiallyzero, i.e. the value of the conductance has reached a substantiallyconstant value, then the tissue change is permanent and continuedheating will not have any further effect on the tissue in the path beingmeasured. The irreversible thermal effect on tissue conductance (the“tissue effect”) can then be determined.

When it is time to treat the diseased tissue, the device can beprogrammed to measure the far field tissue conductance, i.e. theconductance between adjacent leads, both between electrode surfaces atthe same depth in the tissue i.e. straight through the tissue, andbetween electrode surfaces at different depths in the tissue, i.e.diagonally, while the tissue is being heated.

When proportionally the same irreversible tissue effect has measured inall of these far field conductance paths (i.e. the change in conductancewhich is proportional to the length of each electrical path beingmeasured) then this means that the tissue in all the conductance pathsbetween the leads has been heated to the temperature where cell depthshould have occurred. This means that the heat treatment is complete andcan be terminated. Preferably this is signaled to an operator by avisual and/or audible signal such as, but not limited to, a screenmessage, a signal lamp, a bell, a chime or the like.

While the invention has been illustrated by devices and methods in whichconductance or a transfer function is measured and the resultingmeasurements analysed, it is also conceivable to modify devices andmethods in accordance with the present invention to use measurementsrelating to impedance and/or capacitance instead.

While the invention has been illustrated with examples in which aheating element (e.g. a laser light transparent window) on a lead isintended to be positioned at a depth inside a tissue, e.g. a tumour,being treated, it is also conceivable to modify devices and methods inaccordance with the present invention so that the heating element ispositioned at or near the boundary of the tumour—for example near to butoutside the tumour.

While the present invention has been illustrated with examples ofmethods and devices in which two or more leads are implanted in apatient, it is conceivable in a further embodiment of the presentinvention that methods and devices may be adapted for use with a singlelead.

While the present invention has been illustrated with examples ofmethods and devices in which a lead comprises two or more electrodesurfaces and two or more thermal sensors, it is conceivable in a furtherembodiment of the present invention to use a lead comprising only oneelectrode surface and/or only one thermal sensor.

It is conceivable in a further embodiment of the present invention toprovide a base unit with a plurality of leads, only one of which isprovided with a movable electrode. In this case this lead is preferablypositioned first and is then used as a reference lead against which theposition of further implanted leads can be determined.

While the invention has been illustrated with lasers as the energysources, it is possible to use any other suitable source of energy, suchas ultrasound transducers, resistive heaters, microwave sources,self-regulating Curie metals, self-regulating positive temperaturecoefficient resistors, heater elements, hot liquids, etc.

While the invention has been illustrated by examples of embodiments inwhich thermal sensors are positioned on electrode surfaces, it is alsoconceivable to position them beside said surfaces or at a short distancefrom them. However the advantage that the conductance and/or transferfunctions measurements can be accurately correlated to the temperatureof the tissue surrounding the electrodes will be diminished as thedistance between thermal sensors and electrodes increases. Additionally,it is conceivable to use a plurality of longitudinally separated thermalsensors in order to determine the temperature gradient along a lead.

Methods and devices in accordance with the present invention aresuitable for use in automated systems for the positioning of implantableleads in a patient and/or for the automated treatment of tissue. In suchsystems a robot arm or the like is intended to insert the leads andrequires information on the actual position of the leads as they arebeing inserted.

The actual position of the leads relative to each other and/or to areference point on the placement system and/or the patient during andafter insertion can be determined by means of the present invention.

Thermal treatment of the tissue may then take place.

In a conceivable use of the present invention for implanting leads intoa patient, the position of at least one lead is monitored by ultrasoundor some other imaging system during implantation in order to confirmthat the lead is indeed being positioned correctly .

In all embodiments of the present invention, leads can be provided witha hollow tube or other distributing means leading to electrodes and/orthermal sensors to allow the addition of a conductive fluid to saidelectrodes and/or thermal sensors in order to ensure good electricaland/or thermal connection with the surrounding tissue. Such adistribution means can be used during thermal treatment to addconductive fluid in order to ensure that changes in tissue geometrycaused by heating, e.g. tissue shrinkage, do not influence measurementstaken using those electrodes and/or thermal sensors.

The above described constructions and methods are for illustrativepurposes only and are not intended to limit the scope of the followingclaims.

1-11. (canceled)
 12. Device for the thermal treatment of tissuecomprising a plurality of implantable electrode surfaces, at least onethermal sensor for measuring temperatures at or near at least one ofsaid electrode surfaces, at least one tissue heating element for heatingtissue, a current generator, measuring means for measuring the value ofan electrical property between selectable pairs of said electrodesurfaces, and a control system for controlling said tissue heatingelements, current generator and measuring device, wherein said devicecomprises memory for storing measured values of said electrical propertymeasured over a period of time and software for processing storedmeasured values in order to determine a calculated value of theelectrical property between at least one selectable pair of electrodesand for determining when the measured electrical property has reached acalculated value.
 13. Device in accordance with claim 12 wherein saidcontrol means is provided with processing software for recordingtemperature and for processing measured temperature values and storedmeasured values of said electrical property in order to calculate thereversible temperature coefficient of said tissue property.
 14. Devicein accordance with claim 12 wherein said control means is provided withprocessing software for recording temperature and for processingmeasured temperature values and stored measured values of saidelectrical property in order to calculate the irreversible temperaturecoefficient of said tissue property.
 15. Device in accordance with claim14 wherein it comprises a display means for displaying informationrelating to said measured electrical property and/or calculatedcoefficients and/or calculated temperature effects.
 16. Device inaccordance with claim 14 wherein conductance is measured at a pluralityof different current frequencies.
 17. Device in accordance with claim 15wherein updated information regarding said measured electrical propertyis displayed to an operator at least once per second.
 18. Device inaccordance with claim 12 wherein it comprises at least one lead having adistal electrode surface, at least one intermediate electrode surfaceand a tissue heating element positioned between said distal electrodesurface and an intermediate electrode surfaces.
 19. Device in accordancewith claim 18 wherein a lead comprises at least two thermal sensors. 20.Method for measuring the electrical property of tissue comprising thefollowing steps: a) activating sources of energy to provide energy to atissue heating element on a lead implanted in said tissue wherein saidimplanted lead comprises at least two thermal sensors for measuring thetemperature of the tissue and at least two electrodes for measuring anelectrical property of said tissue; b) monitoring the temperature sensedby thermal sensors positioned near said tissue heating element andcontrolling the heat provided to tissue heating element so that apredetermined desired temperature is detected and maintained at saidthermal sensors; c) measuring, storing and processing signals relatingto the value of an electrical property between pairs of electrodes; d)deactivating said sources of energy when, after having started changing,said value of an electrical property has ceased to change for apredetermined period of time.
 21. Method in accordance with claim 20comprising the further step of producing a signal that measurement hasbeen terminated.
 22. Method in accordance with claim 20 wherein thereare at least two leads implanted in said tissue, wherein each saidimplanted lead comprises at least two thermal sensors and at least twoelectrodes for measuring an electrical property of said tissue. 23.Software for performing a method in accordance with claim
 20. 24. Methodfor the thermal treatment of tissue comprising the following steps: a)activating a source of energy to provide energy to a tissue heatingelement on a lead implanted in said tissue, wherein said implanted leadcomprises at least two thermal sensors for measuring the temperature ofthe tissue and at least two electrodes for measuring an electricalproperty of said tissue; b) monitoring the temperature sensed by thermalsensors positioned near said tissue heating element and controlling theenergy provided to said tissue heating element so that a predetermineddesired temperature is detected and maintained at said thermal sensors;c) measuring, storing and processing signals relating to the value of anelectrical property between a pair of said electrodes for measuring anelectrical property of said tissue; d) deactivating said sources ofenergy when, after having started changing, said value of an electricalproperty ceases to change for a predetermined period of time.
 25. Methodin accordance with claim 24 comprising the further step of producing asignal that treatment has been terminated.
 26. Method in accordance withclaim 24 wherein said electrical property is impedance.
 27. Method inaccordance with claim 24 wherein there are at least two leads implantedin said tissue, wherein each said implanted lead comprises at least twothermal sensors and at least two electrodes for measuring an electricalproperty of said tissue.
 28. Software for performing a method inaccordance with claim
 24. 29. Device in accordance with claim 13 whereinsaid control means is provided with processing software for recordingtemperature and for processing measured temperature values and storedmeasured values of said electrical property in order to calculate theirreversible temperature coefficient of said tissue property.